Many of the proposed experiments are aimed at the identification of molecules that affect the expression of loci for tissue-specific functions in human cells. Cultured fibroblasts will be exposed to agents which are suspected, on theoretical grounds, of derepressing genes that are normally quiescent in fibroblasts. The agents will include phosphorylated intermediates, and compounds which cause such molecules to accumulate inside the cell. A number of these experiments have been designed to yield also new data about pyrimidine metabolism, and the genetic diseases which derange it. In another study, we shall try to derepress a locus which encodes for tissue-specific protein by incubating cells in a solution containing multiple copies of the gene for the product of that locus. An additional program is aimed at the isolation of auxotrophic mutants of cultured cells, whose respective cellular phenotypes resemble those seen in several hereditary diseases. The mutant cells will be obtained by exposing a population of cells to mutagens, and selecting with metabolic analogues, for enzyme-deficient variants. Two other programs proposed are designed to apply recent information on pyrimidine metabolism to medical problems. In one of these programs, recent theories about the mechanism whereby cancer cells escape the growth-inhibiting effects of chemotherapeutic agents will be tested. Both cultured cells and animals inoculated with transplantable tumors will be employed in these studies. In a second applied program, theories concerning the molecular basis for the hypnotic and addicting properties of the barbiturates, and structurally similar drugs, will be tested. The effect of these drugs on specific enzymes in brain extracts will be measured. Finally, cell strains will be developed from infants and children with pancytopenia, and the cells will be grown both in a minimal tissue culture medium and in a complete one. A search will be conducted for patients whose cells grow in a complete medium, but not in the minimal one -- a finding which would suggest that genetic auxotrophy is the cause of the disease.